The present invention reports to the therapeutic chemistry domain and more particularly to pharmacotechny.
It is more precisely related to new pharmaceutical compositions with laxative properties whom the main characteristic is to contain an effervescent mixture producing fast and gradually carbon dioxide.
The invention specifically reports to new pharmaceutical compositions designed for the rectal route able to producing by a chemical reaction active principles in contact with humidity existing in the rectal ampule an important and quick gaseous release.
The French patent number 788.198 (Waldenmeyer J. G.) has already described a process to obtain effervescent suppositories which offer the possibility to release native carbon dioxide under action of humidity, heat or any other reason in which the raw materials releasing this acid by their mixing are coated for protection in a greasy substance which thus avoid a premature chemical reaction and consequently protect against decomposition.
Meanwhile these suppositories contain in their bulk, hydrophilic ingredients which allow to the biologic fluids to penetrate into the bulk and allow the start of the chemical reaction which involves the physiologic effect.
Later on the French patent application number 94.11913 filled on Oct. 5, 1994 by the Applicant has described a new process to manufacture such effervescent suppositories on a potassium tartrate acid and sodium bicarbonate basis, stable during preservation.
The problem which occurred for the realization of suppositories described in the previous literature has been to be able to form a sufficiently effervescent bulk, i.e. to release a sufficiently important volume of carbonic gas in a sufficiently reduced set of time to obtain a marked distension of coasts of the rectal ampoule, which produce a relieving reflex.
Different solutions exist to try to solve this problem. The first solution consists to enhance the amount of reactive active principles to increase the released volume of carbonic gas. Meanwhile the size of a suppository rapidly reaches a limit and so it is not possible to incorporate more active ingredients without changing the conservation and homogeneity of the suppositories.
The other solution consists to incorporate into the mass of the pharmaceutical composition intended to the rectal route, another acid component more reactive than potassium acid tartrate and offering all the required guarantees about local tolerance and lack of toxicological risk whom the limit remains in the necessity to do not generate a too coarse release of carbon dioxide.
This solution lies as a basis for the invention which is the subject of the present application.
Therefore the invention consists in pharmaceutical compositions intended to the rectal route, formed with an effervescent mixture consisting of an alkali-metal bicarbonate and a determined acid reactive compound, selected in the group formed by monosodium or monopotassium phosphate, monosodium citrate, pyroglutamic acid and glutamic acid, associated or admixed with one or more diluents or vehicles adapted to the realization of a pharmaceutical form intended to the rectal route.
The effervescent formulation calls for the presence of an alkaline element liable to release easily carbonic gas by a chemical reaction with an acid compound. The experiment shows that with alkaline or alkaline earth metal or others metals carbonates, the reaction is much slower and rarely complete in a relatively short set of time. By another way the selection of the acid compound needs to take considerations of two conditions. This acid compound must not be irritant or toxic on the one hand, and does not launch a too violent or fast effervescent reaction in contact with the alkaline agent. There are only a limited number of acid compounds which satisfy to these both conditions. Among the factors which can involve for the respect of these conditions, there is firstly the pka of the used acid compound and on the other hand the solubility of the acid compound in water or in the biological environment. Thus, a compound like benzoic phtalimide or succinimide due to their low solubility in water only induces a reduced and delayed release. It is also possible that their low degree of acidity play some part.
At the contrary the incorporation in the mixture of strong acid compounds or very soluble acids in aqueous mediums lead to a very strong or too fast gaseous release which exclude the use of such compounds.
Thus, it is not possible to use any acid compound if it does not fall into the category defined above and this fact requires a preliminary adjustment to determine whether the acidic compound is suitable for such a use.
About pharmaceutical compositions intended to the rectal use suppositories made with a synthetic or natural greasy matrix are indicated firstly, and also rectal capsules realized with gelatine. Others solid or coated forms of administration by rectal route, can also be considered.
According to the needs, the acid compound content will be that which also approximately agrees on the molar level with the formulation defined in the previous application in France number 94.11913 by the applicant, namely 1.150 g potassium acid tartrate with 0.700 g of bicarbonate sodium for an adult suppository, i.e. preferably between 1.15 g and 1.20 g, 1.184 g for monosodium phosphate, between 1.25 and 1.30 g and preferably 1.2847 g for monosodium citrate, or for a diacid substance as glutamic acid, between 0.85 and 0.90 g and preferably 0.878 g and for pyroglutamic acid between 0.85 and 0.90 g and preferably 0.889 g. Under these conditions the mixture is able to release a measured volume of CO2 determined with the Bernard""s calcimeter, under atmospheric pressure, about 100 to 120 ml for a suppository during 20 minutes.
The study of the carbonic gas release shows that during the first five minutes a maximal gaseous release occurred which represents about 80% of the total release. Then the release slows down to reach an asymptomatic value after 10 minutes, and after 20 minutes the variations of volume become very small. Depending on the nature of the acid agent, this gaseous release can be very fast and nearly complete after 5 minutes or on the contrary remaining small and needing more than 40 minutes to reach its achievement. Therefore, it is between these two utmost values that the therapeutic optimum takes place.
This invention is also related to a process of realization of pharmaceutical compositions intended for the rectal route, which consist to blend an acid reactive salt selected among monosodium phosphate, monopotassium phosphate, monosodium citrate, pyroglutamic acid and glutamic acid and an alkali-metal bicarbonate with an hydrophilic excipient then to an opacifiant agent and this mixture is introduced in a fusible greasy excipient near the body temperature.
In a particular mode of realization, the hydrophilic excipient is preferably an animal or vegetable lecithin, as for example Soya lecithin or yolk lecithins.
The opacifiant agent is a mineral product, in a powder form, insoluble in the hydrophilic excipient and in the greasy excipient. The opacifiant agent will be preferably an aluminium silicate, a magnesium silicate, a titan oxide or silica.
The greasy excipient is a grease with a melting point lying around 40xc2x0 C., like cocoa-butter, shea butter, Bassia longifolia (Oleum bassiae) butter or mixtures of them or a polyacohol stearate like a semi-synthetic or synthetic polyethyleneglycol or glyceryl stearate, the melting point of which is situated in this temperature range like polyethyleneglycol stearate commercialised under the denomination Trade Name LABRAFIL and semi-synthetic glycerids described in the French Pharmacopea 10th edition and commercialised under the appellation Trade Name SUPPOCIRE(copyright) . . .
Considering rectal capsules, greasy excipient is not used or only in small amounts to secure an homogeneous solid bulk. This preparation is introduced into a gelatine capsule the thickness of which varies from 1 to 3 mm.